ClinVar Miner

Submissions for variant NM_007194.4(CHEK2):c.1534C>G (p.Leu512Val) (rs17882942)

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Total submissions: 9
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130543 SCV000185412 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-13 criteria provided, single submitter clinical testing The p.L512V variant (also known as c.1534C>G), located in coding exon 13 of the CHEK2 gene, results from a C to G substitution at nucleotide position 1534. The leucine at codon 512 is replaced by valine, an amino acid with highly similar properties. This alteration was reported in 1/1303 breast cancer patients and was not observed in 1109 controls (Le Calvez-Kelm F et al. Breast Cancer Res., 2011 Jan;13:R6). This alteration was also reported in a study of 1297 cases of early-onset breast cancer and 1121 controls (Young EL et al. J. Med. Genet., 2016 06;53:366-76). This alteration behaved as functional in an in vivo, yeast-based growth rate assay (Delimitsou A et al. Hum. Mutat., 2019 05;40:631-648). This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000197078 SCV000254930 uncertain significance Familial cancer of breast 2020-10-28 criteria provided, single submitter clinical testing This sequence change replaces leucine with valine at codon 512 of the CHEK2 protein (p.Leu512Val). The leucine residue is weakly conserved and there is a small physicochemical difference between leucine and valine. This variant is present in population databases (rs17882942, ExAC 0.05%). This variant has been reported in individuals affected with breast cancer (PMID: 21244692, 25186627). ClinVar contains an entry for this variant (Variation ID: 141856). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000587712 SCV000278931 uncertain significance not provided 2018-09-12 criteria provided, single submitter clinical testing This variant is denoted CHEK2 c.1534C>G at the cDNA level, p.Leu512Val (L512V) at the protein level, and results in the change of a Leucine to a Valine (CTA>GTA). This variant has been reported in at least two individuals with breast cancer (Le Calvez-Kelm 2011, Tung 2015). Although this variant was observed in large population cohorts, population data in this region of CHEK2 are not considered reliable due to high pseudogene homology (Lek 2016). This variant is not located in a known functional domain. In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether CHEK2 Leu512Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000197078 SCV000488441 uncertain significance Familial cancer of breast 2016-03-29 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000587712 SCV000698784 uncertain significance not provided 2017-05-15 criteria provided, single submitter clinical testing Variant summary: The CHEK2 c.1534C>G (p.Leu512Val) variant involves the alteration of a non-conserved nucleotide, resulting in a missense substitution in the protein kinase domain (InterPro). 5/5 in silico tools predict benign outcome for this variant. This variant was found in 5/113850 control chromosomes including broad and large population from ExAC at a frequency of 0.0000439, which does not exceed the estimated maximal expected allele frequency of a pathogenic CHEK2 variant (0.0003125). However, it was only found in Latino subpopulation with an allele frequency of 0.000452 (5/11054 chromosomes) which is nearly 1.5 times the estimated maximal expected allele frequency, possibly suggesting that it is a rare population-specific polymorphism. However, in a case-control study, this variant was found in one breast cancer patient but not in controls (Calvez-Kelm_2011). Pathogenic variants in this gene are associated with elevated risk of breast cancer. Whether this variant is a significant risk allele needs to be further investigated. To our knowledge, the variant has not been tested by in vitro/in vivo functional assays. Multiple clinical diagnostic laboratories/reputable databases have classified this variant as uncertain significance. Taken together, this variant is currently classified as VUS-possibly benign.
PreventionGenetics,PreventionGenetics RCV000587712 SCV000806874 uncertain significance not provided 2016-12-12 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764367 SCV000895402 uncertain significance Familial cancer of breast; Li-Fraumeni syndrome 2; Osteosarcoma; Malignant tumor of prostate 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000130543 SCV000911101 likely benign Hereditary cancer-predisposing syndrome 2016-06-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587712 SCV001134160 uncertain significance not provided 2019-07-19 criteria provided, single submitter clinical testing

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